REFERENCES
1. Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74:229-63.
2. Rumgay H, Ferlay J, de Martel C, et al. Global, regional and national burden of primary liver cancer by subtype. Eur J Cancer. 2022;161:108-18.
3. Allemani C, Matsuda T, Di Carlo V, et al.; CONCORD Working Group. Global surveillance of trends in cancer survival 2000-14 (CONCORD-3): analysis of individual records for 37 513 025 patients diagnosed with one of 18 cancers from 322 population-based registries in 71 countries. Lancet. 2018;391:1023-75.
4. Wong GL, Wong VW. Risk prediction of hepatitis B virus-related hepatocellular carcinoma in the era of antiviral therapy. World J Gastroenterol. 2013;19:6515-22.
5. Liu Y, Liu L. Changes in the epidemiology of hepatocellular carcinoma in Asia. Cancers. 2022;14:4473.
6. Eslam M, Newsome PN, Sarin SK, et al. A new definition for metabolic dysfunction-associated fatty liver disease: an international expert consensus statement. J Hepatol. 2020;73:202-9.
7. Rinella ME, Lazarus JV, Ratziu V, et al.; NAFLD Nomenclature consensus group. A multisociety Delphi consensus statement on new fatty liver disease nomenclature. Hepatology. 2023;78:1966-86.
8. Habibullah M, Jemmieh K, Ouda A, Haider MZ, Malki MI, Elzouki AN. Metabolic-associated fatty liver disease: a selective review of pathogenesis, diagnostic approaches, and therapeutic strategies. Front Med. 2024;11:1291501.
9. Hong S, Sun L, Hao Y, et al. From NAFLD to MASLD: when metabolic comorbidity matters. Ann Hepatol. 2024;29:101281.
10. Hagström H, Vessby J, Ekstedt M, Shang Y. 99% of patients with NAFLD meet MASLD criteria and natural history is therefore identical. J Hepatol. 2024;80:e76-7.
11. Crane H, Gofton C, Sharma A, George J. MAFLD: an optimal framework for understanding liver cancer phenotypes. J Gastroenterol. 2023;58:947-64.
12. Costante F, Airola C, Santopaolo F, Gasbarrini A, Pompili M, Ponziani FR. Immunotherapy for nonalcoholic fatty liver disease-related hepatocellular carcinoma: lights and shadows. World J Gastrointest Oncol. 2022;14:1622-36.
13. Chan SL, Sun HC, Xu Y, et al. The Lancet Commission on addressing the global hepatocellular carcinoma burden: comprehensive strategies from prevention to treatment. Lancet. 2025;406:731-78.
14. Pinter M, Pinato DJ, Ramadori P, Heikenwalder M. NASH and hepatocellular carcinoma: immunology and immunotherapy. Clin Cancer Res. 2023;29:513-20.
15. Yahoo N, Dudek M, Knolle P, Heikenwälder M. Role of immune responses in the development of NAFLD-associated liver cancer and prospects for therapeutic modulation. J Hepatol. 2023;79:538-51.
16. Llovet JM, Pinyol R, Yarchoan M, et al. Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma. Nat Rev Clin Oncol. 2024;21:294-311.
17. Kudo M, Finn RS, Galle PR, et al. IMbrave150: efficacy and safety of atezolizumab plus bevacizumab versus sorafenib in patients with barcelona clinic liver cancer stage b unresectable hepatocellular carcinoma: an exploratory analysis of the phase III study. Liver Cancer. 2023;12:238-50.
18. Peng Y, Wong CC, Yu J. The paradox of immunotherapy in NASH-HCC. Signal Transduct Target Ther. 2021;6:228.
19. Pfister D, Núñez NG, Pinyol R, et al. NASH limits anti-tumour surveillance in immunotherapy-treated HCC. Nature. 2021;592:450-6.
20. Cheu JWS, Wong CCL. The immune microenvironment of steatotic hepatocellular carcinoma: current findings and future prospects. Hepatol Commun. 2024;8:e0516.
21. McLane LM, Abdel-Hakeem MS, Wherry EJ. CD8 T cell exhaustion during chronic viral infection and cancer. Annu Rev Immunol. 2019;37:457-95.
22. Dudek M, Pfister D, Donakonda S, et al. Auto-aggressive CXCR6+ CD8 T cells cause liver immune pathology in NASH. Nature. 2021;592:444-9.
23. Li M, Wang L, Cong L, et al. Spatial proteomics of immune microenvironment in nonalcoholic steatohepatitis-associated hepatocellular carcinoma. Hepatology. 2024;79:560-74.
24. Pan Y, Chen H, Zhang X, et al. METTL3 drives NAFLD-related hepatocellular carcinoma and is a therapeutic target for boosting immunotherapy. Cell Rep Med. 2023;4:101144.
25. Valenzuela-Pérez L, Kim Lee HS, Bayer RL, et al. CD4+ T cells promote fibrosis during metabolic dysfunction-associated steatohepatitis. bioRxiv. 2025.
26. Brown ZJ, Fu Q, Ma C, et al. Carnitine palmitoyltransferase gene upregulation by linoleic acid induces CD4+ T cell apoptosis promoting HCC development. Cell Death Dis. 2018;9:620.
27. Schneider C, Teufel A, Yevsa T, et al. Adaptive immunity suppresses formation and progression of diethylnitrosamine-induced liver cancer. Gut. 2012;61:1733-43.
28. Miao Y, Li Z, Feng J, et al. The role of CD4+T cells in nonalcoholic steatohepatitis and hepatocellular carcinoma. Int J Mol Sci. 2024;25:6895.
29. Ohkura N, Sakaguchi S. Transcriptional and epigenetic basis of Treg cell development and function: its genetic anomalies or variations in autoimmune diseases. Cell Res. 2020;30:465-74.
30. Ma X, Hua J, Mohamood AR, Hamad AR, Ravi R, Li Z. A high-fat diet and regulatory T cells influence susceptibility to endotoxin-induced liver injury. Hepatology. 2007;46:1519-29.
31. Roh YS, Kim JW, Park S, et al. Toll-like receptor-7 signaling promotes nonalcoholic steatohepatitis by inhibiting regulatory T cells in mice. Am J Pathol. 2018;188:2574-88.
32. Zhang C, Li L, Feng K, Fan D, Xue W, Lu J. ‘Repair’ Treg cells in tissue injury. Cell Physiol Biochem. 2017;43:2155-69.
33. Katz SC, Ryan K, Ahmed N, et al. Obstructive jaundice expands intrahepatic regulatory T cells, which impair liver T lymphocyte function but modulate liver cholestasis and fibrosis. J Immunol. 2011;187:1150-6.
34. Fabregat I, Moreno-Càceres J, Sánchez A, et al.; IT-LIVER Consortium. TGF-β signalling and liver disease. FEBS J. 2016;283:2219-32.
35. Wang H, Zhang H, Wang Y, et al. Regulatory T-cell and neutrophil extracellular trap interaction contributes to carcinogenesis in non-alcoholic steatohepatitis. J Hepatol. 2021;75:1271-83.
36. Behary J, Amorim N, Jiang XT, et al. Gut microbiota impact on the peripheral immune response in non-alcoholic fatty liver disease related hepatocellular carcinoma. Nat Commun. 2021;12:187.
37. Wang H, Tsung A, Mishra L, Huang H. Regulatory T cell: a double-edged sword from metabolic-dysfunction-associated steatohepatitis to hepatocellular carcinoma. EBioMedicine. 2024;101:105031.
38. Hindson J. T cells in NASH and liver cancer: pathology and immunotherapy. Nat Rev Gastroenterol Hepatol. 2021;18:367.
39. Wolf MJ, Adili A, Piotrowitz K, et al. Metabolic activation of intrahepatic CD8+ T cells and NKT cells causes nonalcoholic steatohepatitis and liver cancer via cross-talk with hepatocytes. Cancer Cell. 2014;26:549-64.
40. Clària J. Natural killer cell recognition and killing of activated hepatic stellate cells. Gut. 2012;61:792-3.
41. Tang W, Zhou J, Yang W, et al. Aberrant cholesterol metabolic signaling impairs antitumor immunosurveillance through natural killer T cell dysfunction in obese liver. Cell Mol Immunol. 2022;19:834-47.
42. Xu J, Xia Q, Wu T, et al. Prophylactic treatment with Bacteroides uniformis and Bifidobacterium bifidum counteracts hepatic NK cell immune tolerance in nonalcoholic steatohepatitis induced by high fat diet. Gut Microbes. 2024;16:2302065.
43. Martínez-Chantar ML, Delgado TC, Beraza N. Revisiting the role of natural killer cells in non-alcoholic fatty liver disease. Front Immunol. 2021;12:640869.
44. Hunter S, Willcox CR, Davey MS, et al. Human liver infiltrating γδ T cells are composed of clonally expanded circulating and tissue-resident populations. J Hepatol. 2018;69:654-65.
45. Harley IT, Stankiewicz TE, Giles DA, et al. IL-17 signaling accelerates the progression of nonalcoholic fatty liver disease in mice. Hepatology. 2014;59:1830-9.
46. Zhan C, Peng C, Wei H, Wei K, Ou Y, Zhang Z. Diverse subsets of γδT cells and their specific functions across liver diseases. Int J Mol Sci. 2025;26:2778.
47. Li F, Hao X, Chen Y, et al. The microbiota maintain homeostasis of liver-resident γδT-17 cells in a lipid antigen/CD1d-dependent manner. Nat Commun. 2017;7:13839.
48. Marinović S, Lenartić M, Mladenić K, et al. NKG2D-mediated detection of metabolically stressed hepatocytes by innate-like T cells is essential for initiation of NASH and fibrosis. Sci Immunol. 2023;8:eadd1599.
49. Li Y, You Z, Tang R, Ma X. Tissue-resident memory T cells in chronic liver diseases: phenotype, development and function. Front Immunol. 2022;13:967055.
50. Koda Y, Teratani T, Chu PS, et al. CD8+ tissue-resident memory T cells promote liver fibrosis resolution by inducing apoptosis of hepatic stellate cells. Nat Commun. 2021;12:4474.
51. Gupta PK, Godec J, Wolski D, et al. CD39 expression identifies terminally exhausted CD8+ T cells. PLoS Pathog. 2015;11:e1005177.
52. Li Y, Huang B, Jiang X, et al. Mucosal-associated invariant T cells improve nonalcoholic fatty liver disease through regulating macrophage polarization. Front Immunol. 2018;9:1994.
53. Toubal A, Kiaf B, Beaudoin L, et al. Mucosal-associated invariant T cells promote inflammation and intestinal dysbiosis leading to metabolic dysfunction during obesity. Nat Commun. 2020;11:3755.
54. Deschler S, Pohl-Topcu J, Ramsauer L, et al. Polyunsaturated fatty acid-induced metabolic exhaustion and ferroptosis impair the anti-tumour function of MAIT cells in MASLD. J Hepatol. 2025;83:1364-78.
55. Karl M, Hasselwander S, Zhou Y, et al. Dual roles of B lymphocytes in mouse models of diet-induced nonalcoholic fatty liver disease. Hepatology. 2022;76:1135-49.
56. Xie Y, Huang Y, Li ZY, et al. Interleukin-21 receptor signaling promotes metabolic dysfunction-associated steatohepatitis-driven hepatocellular carcinoma by inducing immunosuppressive IgA+ B cells. Mol Cancer. 2024;23:95.
57. Huang Y, Xie Y, Zhang Y, et al. Single-cell transcriptome reveals the reprogramming of immune microenvironment during the transition from MASH to HCC. Mol Cancer. 2025;24:177.
58. Petriv N, Suo H, Hochnadel I, et al. Essential roles of B cell subsets in the progression of MASLD and HCC. JHEP Rep. 2024;6:101189.
59. Kotsiliti E, Leone V, Schuehle S, et al. Intestinal B cells license metabolic T-cell activation in NASH microbiota/antigen-independently and contribute to fibrosis by IgA-FcR signalling. J Hepatol. 2023;79:296-313.
60. Barrow F, Khan S, Fredrickson G, et al. Microbiota-driven activation of intrahepatic B cells aggravates NASH through innate and adaptive signaling. Hepatology. 2021;74:704-22.
61. Wang H, Herman A, Barrow F, et al. Single-cell RNA sequencing reveals a reprogramming of hepatic immune cells and a protective role for B cells in MASH-driven HCC. Hepatol Commun. 2025;9:e0668.
62. Zhang P, Chen Z, Kuang H, et al. Neuregulin 4 suppresses NASH-HCC development by restraining tumor-prone liver microenvironment. Cell Metab. 2022;34:1359-76.e7.
63. Batlle E, Massagué J. Transforming growth factor-β signaling in immunity and cancer. Immunity. 2019;50:924-40.
64. Foglia B, Sutti S, Cannito S, et al. Histidine-rich glycoprotein in metabolic dysfunction-associated steatohepatitis-related disease progression and liver carcinogenesis. Front Immunol. 2024;15:1342404.
65. Liang Y, Zhang R, Biswas S, et al. Integrated single-cell transcriptomics reveals the hypoxia-induced inflammation-cancer transformation in NASH-derived hepatocellular carcinoma. Cell Prolif. 2024;57:e13576.
66. Zhou L, Qiu X, Meng Z, et al. Hepatic danger signaling triggers TREM2+ macrophage induction and drives steatohepatitis via MS4A7-dependent inflammasome activation. Sci Transl Med. 2024;16:eadk1866.
67. Zhang Y, Luo Y, Liu X, et al. NCOA5 haploinsufficiency in myeloid-lineage cells sufficiently causes nonalcoholic steatohepatitis and hepatocellular carcinoma. Cell Mol Gastroenterol Hepatol. 2024;17:1-27.
68. Clement CC, Nanaware PP, Yamazaki T, et al. Pleiotropic consequences of metabolic stress for the major histocompatibility complex class II molecule antigen processing and presentation machinery. Immunity. 2021;54:721-36.e10.
69. Shi X, Zheng Q, Wang X, et al. Compromised macrophages contribute to progression of MASH to hepatocellular carcinoma in FGF21KO mice. Sci Adv. 2024;10:eado9311.
70. Rose JP, Morgan DA, Sullivan AI, et al. FGF21 reverses MASH through coordinated actions on the CNS and liver. Cell Metab. 2025;37:1515-29.e6.
71. Mohammed S, Thadathil N, Ohene-Marfo P, et al. Absence of either Ripk3 or Mlkl reduces incidence of hepatocellular carcinoma independent of liver fibrosis. Mol Cancer Res. 2023;21:933-46.
72. Naugler WE, Sakurai T, Kim S, et al. Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science. 2007;317:121-4.
73. Wu XQ, Ying F, Chung KPS, et al. Intestinal Akkermansia muciniphila complements the efficacy of PD1 therapy in MAFLD-related hepatocellular carcinoma. Cell Rep Med. 2025;6:101900.
74. Min BH, Devi S, Kwon GH, et al. Gut microbiota-derived indole compounds attenuate metabolic dysfunction-associated steatotic liver disease by improving fat metabolism and inflammation. Gut Microbes. 2024;16:2307568.
75. Su T, He Y, Wang M, et al. Macrophage-hepatocyte circuits mediated by grancalcin aggravate the progression of metabolic dysfunction associated steatohepatitis. Adv Sci. 2024;11:e2406500.
76. Hu S, Li R, Gong D, et al. Atf3-mediated metabolic reprogramming in hepatic macrophage orchestrates metabolic dysfunction-associated steatohepatitis. Sci Adv. 2024;10:eado3141.
77. Jaitin DA, Adlung L, Thaiss CA, et al. Lipid-associated macrophages control metabolic homeostasis in a Trem2-dependent manner. Cell. 2019;178:686-98.e14.
78. Vennin C, Cattaneo CM, Bosch L, et al. Taxanes trigger cancer cell killing in vivo by inducing non-canonical T cell cytotoxicity. Cancer Cell. 2023;41:1170-85.e12.
79. Kohlhepp MS, Liu H, Tacke F, Guillot A. The contradictory roles of macrophages in non-alcoholic fatty liver disease and primary liver cancer - challenges and opportunities. Front Mol Biosci. 2023;10:1129831.
80. Leslie J, Mackey JBG, Jamieson T, et al. CXCR2 inhibition enables NASH-HCC immunotherapy. Gut. 2022;71:2093-106.
81. Kwak JW, Houghton AM. Targeting neutrophils for cancer therapy. Nat Rev Drug Discov. 2025;24:666-84.
82. Zhang P, Liu D, Wu L, et al. Neutrophil serine proteases NE and PR3 controlled by the miR-223/STAT3 axis potentiate MASH and liver fibrosis. Hepatology. 2025.
83. Xu M, Xu H, Ling YW, et al. Neutrophil extracellular traps-triggered hepatocellular senescence exacerbates lipotoxicity in non-alcoholic steatohepatitis. J Adv Res. 2025:S2090-1232(25)00175-4.
84. Xia Y, Wang Y, Xiong Q, et al. Neutrophil extracellular traps promote MASH fibrosis by metabolic reprogramming of HSC. Hepatology. 2025;81:947-61.
85. Babuta M, Morel C, de Carvalho Ribeiro M, et al. Neutrophil extracellular traps activate hepatic stellate cells and monocytes via NLRP3 sensing in alcohol-induced acceleration of MASH fibrosis. Gut. 2024;73:1854-69.
86. Tu T, Hong H, Alhousari D, et al. Proinflammatory macrophages release CXCL5 to regulate T cell function and limit effects of αPD-1 in steatosis-driven liver cancer. JHEP Rep. 2025;7:101385.
87. Teo JMN, Chen Z, Chen W, et al. Tumor-associated neutrophils attenuate the immunosensitivity of hepatocellular carcinoma. J Exp Med. 2025:222.
88. Deczkowska A, David E, Ramadori P, et al. XCR1+ type 1 conventional dendritic cells drive liver pathology in non-alcoholic steatohepatitis. Nat Med. 2021;27:1043-54.
89. Merad M, Sathe P, Helft J, Miller J, Mortha A. The dendritic cell lineage: ontogeny and function of dendritic cells and their subsets in the steady state and the inflamed setting. Annu Rev Immunol. 2013;31:563-604.
90. Haas JT, Vonghia L, Mogilenko DA, et al. Transcriptional network analysis implicates altered hepatic immune function in NASH development and resolution. Nat Metab. 2019;1:604-14.
91. Seyhan D, Allaire M, Fu Y, et al. Immune microenvironment in hepatocellular carcinoma: from pathogenesis to immunotherapy. Cell Mol Immunol. 2025;22:1132-58.
92. Heier EC, Meier A, Julich-Haertel H, et al. Murine CD103+ dendritic cells protect against steatosis progression towards steatohepatitis. J Hepatol. 2017;66:1241-50.
93. Gabrilovich DI, Bronte V, Chen SH, et al. The terminology issue for myeloid-derived suppressor cells. Cancer Res. 2007;67:425; author reply 426.
95. Condamine T, Ramachandran I, Youn JI, Gabrilovich DI. Regulation of tumor metastasis by myeloid-derived suppressor cells. Annu Rev Med. 2015;66:97-110.
96. Safarzadeh E, Orangi M, Mohammadi H, Babaie F, Baradaran B. Myeloid-derived suppressor cells: important contributors to tumor progression and metastasis. J Cell Physiol. 2018;233:3024-36.
97. Wang L, Zhu L, Liang C, et al. Targeting N6-methyladenosine reader YTHDF1 with siRNA boosts antitumor immunity in NASH-HCC by inhibiting EZH2-IL-6 axis. J Hepatol. 2023;79:1185-200.
98. Wen J, Zhang X, Wong CC, et al. Targeting squalene epoxidase restores anti-PD-1 efficacy in metabolic dysfunction-associated steatohepatitis-induced hepatocellular carcinoma. Gut. 2024;73:2023-36.
99. Giraud J, Chalopin D, Ramel E, et al. THBS1+ myeloid cells expand in SLD hepatocellular carcinoma and contribute to immunosuppression and unfavorable prognosis through TREM1. Cell Rep. 2024;43:113773.
100. Zheng C, Zheng L, Yoo JK, et al. Landscape of infiltrating T cells in liver cancer revealed by single-cell sequencing. Cell. 2017;169:1342-56.e16.
101. Finn RS, Qin S, Ikeda M, et al.; IMbrave150 Investigators. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020;382:1894-905.
102. Zayac A, Almhanna K. Hepatobiliary cancers and immunotherapy: where are we now and where are we heading? Transl Gastroenterol Hepatol. 2020;5:8.
103. Bruix J, Chan SL, Galle PR, Rimassa L, Sangro B. Systemic treatment of hepatocellular carcinoma: an EASL position paper. J Hepatol. 2021;75:960-74.
104. Cheng AL, Qin S, Ikeda M, et al. Updated efficacy and safety data from IMbrave150: atezolizumab plus bevacizumab vs. sorafenib for unresectable hepatocellular carcinoma. J Hepatol. 2022;76:862-73.
105. Galle PR, Finn RS, Qin S, et al. Patient-reported outcomes with atezolizumab plus bevacizumab versus sorafenib in patients with unresectable hepatocellular carcinoma (IMbrave150): an open-label, randomised, phase 3 trial. Lancet Oncol. 2021;22:991-1001.
106. Abou-Alfa GK, Lau G, Kudo M, et al. Tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. NEJM Evid. 2022;1:EVIDoa2100070.
107. Rimassa L, Chan SL, Sangro B, et al. Five-year overall survival update from the HIMALAYA study of tremelimumab plus durvalumab in unresectable HCC. J Hepatol. 2025;83:899-908.
108. Ren Z, Xu J, Bai Y, et al.; ORIENT-32 study group. Sintilimab plus a bevacizumab biosimilar (IBI305) versus sorafenib in unresectable hepatocellular carcinoma (ORIENT-32): a randomised, open-label, phase 2-3 study. Lancet Oncol. 2021;22:977-90.
109. Yau T, Park JW, Finn RS, et al. Nivolumab versus sorafenib in advanced hepatocellular carcinoma (CheckMate 459): a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol. 2022;23:77-90.
110. Zhu AX, Finn RS, Edeline J, et al.; KEYNOTE-224 investigators. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. Lancet Oncol. 2018;19:940-52.
111. Finn RS, Ryoo BY, Merle P, et al.; KEYNOTE-240 investigators. Pembrolizumab as second-line therapy in patients with advanced hepatocellular carcinoma in KEYNOTE-240: a randomized, double-blind, phase III trial. J Clin Oncol. 2020;38:193-202.
112. Finn RS, Gu K, Chen X, et al. Second-line pembrolizumab for advanced HCC: meta-analysis of the phase III KEYNOTE-240 and KEYNOTE-394 studies. JHEP Rep. 2025;7:101350.
113. Kudo M, Matilla A, Santoro A, et al. CheckMate 040 cohort 5: a phase I/II study of nivolumab in patients with advanced hepatocellular carcinoma and Child-Pugh B cirrhosis. J Hepatol. 2021;75:600-9.
114. Yau T, Kang YK, Kim TY, et al. Efficacy and safety of nivolumab plus ipilimumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib: the CheckMate 040 randomized clinical trial. JAMA Oncol. 2020;6:e204564.
115. Yau T, Galle PR, Decaens T, et al.; CheckMate 9DW investigators. Nivolumab plus ipilimumab versus lenvatinib or sorafenib as first-line treatment for unresectable hepatocellular carcinoma (CheckMate 9DW): an open-label, randomised, phase 3 trial. Lancet. 2025;405:1851-64.
116. Yau T, Park J, Finn R, et al. CheckMate 459: a randomized, multi-center phase III study of nivolumab (NIVO) vs sorafenib (SOR) as first-line (1L) treatment in patients (pts) with advanced hepatocellular carcinoma (aHCC). Ann Oncol. 2019;30:v874-5.
117. Kelley R, Yau T, Cheng A, et al. VP10-2021: Cabozantinib (C) plus atezolizumab (A) versus sorafenib (S) as first-line systemic treatment for advanced hepatocellular carcinoma (aHCC): results from the randomized phase III COSMIC-312 trial. Ann Oncol. 2022;33:114-6.
118. Zhu AX, Kang YK, Yen CJ, et al.; REACH-2 study investigators. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019;20:282-96.
119. Abou-Alfa GK, Meyer T, Cheng AL, et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med. 2018;379:54-63.
120. Abou-Alfa GK, Chan SL, Kudo M, et al. Phase 3 randomized, open-label, multicenter study of tremelimumab (T) and durvalumab (D) as first-line therapy in patients (pts) with unresectable hepatocellular carcinoma (uHCC): HIMALAYA. J Clin Oncol. 2022;40:379.
121. Rimini M, Rimassa L, Ueshima K, et al. Atezolizumab plus bevacizumab versus lenvatinib or sorafenib in non-viral unresectable hepatocellular carcinoma: an international propensity score matching analysis. ESMO Open. 2022;7:100591.
122. Meyer T, Galani S, Lopes A, Vogel A. Aetiology of liver disease and response to immune checkpoint inhibitors: an updated meta-analysis confirms benefit in those with non-viral liver disease. J Hepatol. 2023;79:e73-6.
123. Akce M, Zaidi MY, Waller EK, El-Rayes BF, Lesinski GB. The potential of CAR T cell therapy in pancreatic cancer. Front Immunol. 2018;9:2166.
124. Wu X, Jin B, Liu X, Mao Y, Wan X, Du S. Research trends of cellular immunotherapy for primary liver cancer: a bibliometric analysis. Hum Vaccin Immunother. 2024;20:2426869.
125. Tian Y, Li Y, Shao Y, Zhang Y. Gene modification strategies for next-generation CAR T cells against solid cancers. J Hematol Oncol. 2020;13:54.
126. Shi Y, Shi D, Chi J, et al. Combined local therapy and CAR-GPC3 T-cell therapy in advanced hepatocellular carcinoma: a proof-of-concept treatment strategy. Cancer Commun. 2023;43:1064-8.
127. Steffin D, Ghatwai N, Montalbano A, et al. Interleukin-15-armoured GPC3 CAR T cells for patients with solid cancers. Nature. 2025;637:940-6.
128. Liu L, Shah K. The potential of the gut microbiome to reshape the cancer therapy paradigm: a review. JAMA Oncol. 2022;8:1059-67.
129. Guo Z, Yao Z, Huang B, et al. MAFLD-related hepatocellular carcinoma: exploring the potent combination of immunotherapy and molecular targeted therapy. Int Immunopharmacol. 2024;140:112821.
130. Lau HCH, Zhang X, Yu J. Gut microbiome in metabolic dysfunction-associated steatotic liver disease and associated hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol. 2025;22:619-38.
131. Craven L, Rahman A, Nair Parvathy S, et al. Allogenic fecal microbiota transplantation in patients with nonalcoholic fatty liver disease improves abnormal small intestinal permeability: a randomized control trial. Am J Gastroenterol. 2020;115:1055-65.
132. Xue L, Deng Z, Luo W, He X, Chen Y. Effect of fecal microbiota transplantation on non-alcoholic fatty liver disease: a randomized clinical trial. Front Cell Infect Microbiol. 2022;12:759306.
133. Aller R, De Luis DA, Izaola O et al. Effect of a probiotic on liver aminotransferases in nonalcoholic fatty liver disease patients: a double blind randomized clinical trial. Eur Rev Med Pharmacol Sci. 2011;15:1090-5.
134. Zhu W, Yan M, Cao H, Zhou J, Xu Z. Effects of Clostridium butyricum capsules combined with rosuvastatin on intestinal flora, lipid metabolism, liver function and inflammation in NAFLD patients. Cell Mol Biol. 2022;68:64-9.
135. Loguercio C, Federico A, Tuccillo C, et al. Beneficial effects of a probiotic VSL#3 on parameters of liver dysfunction in chronic liver diseases. J Clin Gastroenterol. 2005;39:540-3.
136. Hai S, Li X, Xie E, et al. Intestinal IL-33 promotes microbiota-derived trimethylamine N-oxide synthesis and drives metabolic dysfunction-associated steatotic liver disease progression by exerting dual regulation on HIF-1α. Hepatology. 2025;82:184-98.
137. Zhu X, Hu M, Huang X, et al. Interplay between gut microbial communities and metabolites modulates pan-cancer immunotherapy responses. Cell Metab. 2025;37:806-23.e6.
138. Friedman SL, Neuschwander-Tetri BA, Rinella M, Sanyal AJ. Mechanisms of NAFLD development and therapeutic strategies. Nat Med. 2018;24:908-22.
139. Bian H, Liu YM, Chen ZN. New avenues for NASH therapy by targeting ACC. Cell Metab. 2022;34:191-3.
140. Dong L, Lou W, Xu C, Wang J. Naringenin cationic lipid-modified nanoparticles mitigate MASLD progression by modulating lipid homeostasis and gut microbiota. J Nanobiotechnology. 2025;23:168.
141. Zhang Y, Wang X, Lin J, et al. A microbial metabolite inhibits the HIF-2α-ceramide pathway to mediate the beneficial effects of time-restricted feeding on MASH. Cell Metab. 2024;36:1823-38.e6.
142. Bao J, Zhao Y, Xu X, Ling S. Advances in the use of metformin for liver disease. Curr Med Chem. 2025;32:3591-605.
143. Wabitsch S, McCallen JD, Kamenyeva O, et al. Metformin treatment rescues CD8+ T-cell response to immune checkpoint inhibitor therapy in mice with NAFLD. J Hepatol. 2022;77:748-60.
144. Mossmann D, Müller C, Park S, et al. Arginine reprograms metabolism in liver cancer via RBM39. Cell. 2023;186:5068-83.e23.
145. Chang Y, Wang N, Li S, et al. SLC3A2-mediated lysine uptake by cancer cells restricts T-cell activity in hepatocellular carcinoma. Cancer Res. 2025;85:2250-67.
146. Guo H, Wang M, Ni C, et al. TREM2 promotes the formation of a tumor-supportive microenvironment in hepatocellular carcinoma. J Exp Clin Cancer Res. 2025;44:20.
147. Qiu H, Shao Z, Wen X, et al. TREM2: keeping pace with immune checkpoint inhibitors in cancer immunotherapy. Front Immunol. 2021;12:716710.
148. Allard B, Jacoberger-Foissac C, Cousineau I, et al. Adenosine A2A receptor is a tumor suppressor of NASH-associated hepatocellular carcinoma. Cell Rep Med. 2023;4:101188.
149. Yu H, Pardoll D, Jove R. STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer. 2009;9:798-809.
150. Fu JT, Liu J, Wu WB, et al. Targeting EFHD2 inhibits interferon-γ signaling and ameliorates non-alcoholic steatohepatitis. J Hepatol. 2024;81:389-403.
151. Gu L, Zhu Y, Lee M, et al. Angiotensin II receptor inhibition ameliorates liver fibrosis and enhances hepatocellular carcinoma infiltration by effector T cells. Proc Natl Acad Sci U S A. 2023;120:e2300706120.
152. Qiu X, Gao F, Wang K, Zhang Z, Shao C, Xu X. Aspirin in hepatocellular carcinoma: is it an out-of-date or promising treatment? ILIVER. 2022;1:55-64.
153. Fan H, Wang R, Wen B, Xiong J. Biomarkers and potential therapeutic targets driving progression of non-alcoholic steatohepatitis to hepatocellular carcinoma predicted through transcriptomic analysis. Front Immunol. 2024;15:1502263.
154. Zou W, Huo B, Tu Y, et al. Metabolic reprogramming by chemo-gene co-delivery nanoparticles for chemo-immunotherapy in head and neck squamous cell carcinoma. Acta Biomater. 2025;199:361-73.
155. Deng H, Li Q, Wang B, et al. Reshaping tumor immune microenvironment through ROS-responsive prodrug polyplexes via synergistic effect of CRISPRi system and epigenetic inhibitor for breast cancer therapy. Mater Today Bio. 2025;35:102285.





